Recovery of Synaptic Dysfunction and Memory Loss in Alzheimer's Disease by Selective Co-Activation of Nicotinic Acetylcholine Receptors

通过烟碱乙酰胆碱受体的选择性共激活恢复阿尔茨海默病的突触功能障碍和记忆丧失

基本信息

批准号：
10468170
负责人：
Seonil Kim
金额：
$ 15.2万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-06-30
项目状态：
已结题

项目摘要

Many studies have provided evidences that beta-amyloid peptide (Aβ) triggers synaptic dysfunction and loss of hippocampus-dependent memory in the prodromic stage of Alzheimer’s disease (AD), but the underlying mechanisms remain uncertain. Aβ can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), which elicits synaptic dysfunction in AD. Indeed, the loss of nAChRs is the prominent AD pathology, thus Aβ-induced disruptions of nAChR function underlie deficits in hippocampal synapses, leading to memory loss in AD. However, the effect of Aβ on nAChR physiology is complex - Aβ can act like an agonist or an antagonist on the receptors. Significantly, most of currently prescribed drugs for AD inhibit the general breakdown of acetylcholine (acetylcholinesterase inhibitors), thus potentially stimulates all types of acetylcholine receptors. Importantly, they have only modest efficacy due to non-selective stimulation of acetylcholine receptors given that nearly 30 subtypes of neuronal nAChRs have been reported in the human brain. This suggests distinct nAChR subtypes are differentially affected in AD. Among the three major nAChR subtypes in the hippocampus, α7-, α4β2-, and α3β4-nAChRs, we identify that Aβ selectively affects α7- and α4β2-nAChRs together, but not α3β4-receptors, in cultured mouse hippocampal neurons, resulting in neuronal and synaptic dysfunction, an important characteristic in AD. Moreover, we reveal that selective co-activation of α7- and α4β2-receptors is sufficient to reverse the Aβ effects in cultured hippocampal neurons. Therefore, the overall hypothesis of the proposed work is that selective co-activation of α7 and α4β2 nAChRs reverses Aβ-induced synaptic dysfunction and memory loss in AD. However, isolated neurons do not reflect the nature of the organism due to the isolation and lack of contact with other cells. The significance of the proposed work thus is based on the scientific premise that further studies using intact neural circuits are needed in order to investigate nAChR subtype selectivity of Aβ effects on synaptic function and memory in AD. In the proposed work, we will thus use brain slice electrophysiology and animal behavioral assays to test our hypothesis. Moreover, we will use Tg2576 transgenic mice, one of the most well characterized, and widely used, mouse models of AD. In Aim 1. we will test the hypothesis that selective co-activation of α7- and α4β2-nAChRs reverses Aβ-induced altered synaptic plasticity. In Aim 2, we will determine the hypothesis that selective co-activation of α7- and α4β2-nAChRs improves learning and memory in AD model mice. Given that cholinergic deficiency is associated with AD, strategies aiming to restore normal cholinergic function have been developed as therapeutic drugs for AD. Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for AD so far. Therefore, the idea that selective co-activation of α7- and α4β2-nAChRs in the hippocampus can reverse Aβ effects on AD pathology is a fundamental new concept, which may lead to innovative and novel therapeutic strategies.

许多研究提供了证据表明，β-淀粉样蛋白肽（Aβ）触发突触功能障碍和在阿尔茨海默氏病（AD）的前代阶段，海马依赖性记忆的丧失，但基础机制仍然不确定。 Aβ可以通过与烟碱乙酰胆碱的相互作用来改变神经元信号传导受体（NACHR），引起AD中的突触功能障碍。实际上，nachrs的损失是突出的广告病理学，因此Aβ诱导的NACHR功能的破坏是在海马突触中定义的，导致广告中的内存损失。但是，Aβ对NACHR生理学的影响很复杂-Aβ可以像激动剂一样起作用接收器上的对手。值得注意的是，大多数当前处方药以抑制一般乙酰胆碱（乙酰胆碱酯酶抑制剂）的分解，因此可能刺激所有类型的乙酰胆碱受体。重要的是，由于非选择性刺激乙酰胆碱受体，它们仅具有适度的效率鉴于在人脑中已经报道了将近30个神经元NACHR的亚型。这暗示了不同的 NACHR亚型在AD中受到不同影响。在海马的三个主要NACHR亚型中， α7-，α4β2-和α3β4-NACHRS，我们确定Aβ选择性地影响α7-和α4β2-NACHR，但不同时影响α4β2-NACHR 在培养的小鼠海马神经元中α3β4受体，导致神经元和突触功能障碍，A 广告中的重要特征。此外，我们揭示了α7-和α4β2受体的选择性共激活是足以逆转培养的海马神经元中的Aβ效应。因此，总体假设建议的工作是α7和α4β2NACHR的选择性共激活逆转Aβ诱导的突触功能障碍和广告中的记忆丧失。但是，孤立的神经元不能反映由于隔离而产生的生物的性质并且缺乏与其他细胞的接触。因此，拟议工作的意义基于科学前提为了研究NACHR亚型的选择性，需要进一步使用完整的神经回路的研究 Aβ对AD中突触功能和记忆的影响。在拟议的工作中，我们将使用大脑切片电生理学和动物行为测定法以检验我们的假设。此外，我们将使用TG2576 转基因小鼠是AD的小鼠模型最有特征和广泛使用的小鼠之一。在目标1中。我们将检验以下假设：α7-和α4β2-NACHR的选择性共激活会逆转Aβ诱导的突触改变可塑性。在AIM 2中，我们将确定以下假设：α7-和α4β2-NACHRS的选择性共激活改善AD模型小鼠的学习和记忆。鉴于胆碱能缺乏与AD有关旨在恢复正常胆碱能功能的策略已被开发为AD的治疗药物。不幸的是，到目前为止，没有NACHR化合物证明AD的疾病改良特性。所以，海马中α7-和α4β2-NACHR的选择性共激活可以逆转Aβ对AD的影响的想法病理是一个基本的新概念，可能导致创新和新颖的治疗策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The autism-associated loss of δ-catenin functions disrupts social behavior.

DOI：
10.1073/pnas.2300773120
发表时间：
2023-05-30
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Mendez-Vazquez, Hadassah;Roach, Regan L.;Nip, Kaila;Chanda, Soham;Sathler, Matheus F.;Garver, Tyler;Danzman, Rosaline A.;Moseley, Madeleine C.;Roberts, Jessica P.;Koch, Olivia N.;Steger, Ava A.;Lee, Rahmi;Arikkath, Jyothi;Kim, Seonil
通讯作者：
Kim, Seonil

HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation.

HIV 和 FIV 糖蛋白通过 cGMP 依赖性激酶 II 激活增加细胞 tau 病理学。

DOI：
10.1242/jcs.259764
发表时间：
2022
期刊：
Journal of cell science
影响因子：
4
作者：
Sathler,MatheusF;Doolittle,MichaelJ;Cockrell,JamesA;Nadalin,IndiaR;Hofmann,Franz;VandeWoude,Sue;Kim,Seonil
通讯作者：
Kim,Seonil